Abstract

Cardiac arrest is a leading cause of death in the United States and currently, therapeutic hypothermia, now called targeted temperature management (TTM), is the only recent treatment modality proven to increase survival rates and reduce morbidity for this condition. Shivering and subsequent metabolic stress, however, limits application and benefit of TTM. Stimulating CNS A1 adenosine receptors inhibits shivering and non-shivering thermogenesis in rats and induces a hibernation-like response in hibernating species. Here we investigated the pharmacodynamics of two A1AR agonists in development as anti-shivering agents. To optimize body temperature (Tb) control we evaluated the influence of every-other-day feeding, dose, drug and ambient temperature (Ta) on the Tb lowering effects of N6-cyclohexyladenosine (CHA) and the partial A1AR agonist capadenoson in rats. The highest dose of CHA (1.0 mg/kg, IP) caused all ad libitum fed animals tested to reach our target Tb of 32°C, but responses varied and some rats over-cooled to a Tb as low as 21°C at 17.0°C Ta. Dietary restriction normalized the response to CHA. The partial agonist capadenoson (1.0 or 2.0 mg/kg, IP) produced a more consistent response but the highest dose decreased Tb by only 1.6°C. To prevent overcooling after CHA we studied continuous IV administration in combination with dynamic surface temperature control. Results show that after CHA administration control of surface temperature maintains desired target Tb better than dose or ambient temperature.